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BIOEQUIVALENCE STUDY

(Uji BE)

Yeyet Cahyati Sumirtapura


Pharmaceutic Research Group
School of Pharmacy ITB

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Definition

 Bioequivalence: a term to describe pharmaceutical


equivalent or pharmaceutical alternative products that
display comparable bioavailability when studied under
similar experimental conditions.
 Pharmaceutical equivalence: Drug products in identical
dosage forms that contain the same active ingredient(s), ie,
the same salt or ester, are of the same dosage form, use the
same route of administration, and are identical in strength
or concentration
 Therapeutic equivalence: Drug products are considered to be
therapeutic equivalents if they are pharmaceutical
equivalents and if they can be expected to have the same
clinical effect
Uji Ekivalensi

 Uji Ekivalensi adalah uji in vivo dan/atau in


vitro untuk menentukan ekivalensi antara
obat uji (obat copy) dengan obat
komparator.

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 Uji Ekivalensi in vivo yang selanjutnya disebut Uji
Bioekivalensi adalah uji bioavailabilitas atau
farmakodinamik komparatif yang dirancang untuk
menunjukkan bioekivalensi antara obat uji (obat
copy) dengan obat inovator/komparator.
 Uji Ekivalensi in vitro yang selanjutnya disebut Uji
Disolusi Terbanding adalah uji disolusi komparatif
yang dilakukan untuk menunjukkan similaritas profil
disolusi antara obat uji dengan obat
inovator/komparator.

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Suatu obat copy dikatakan bioekivalen
jika pada pemberian secara in vivo
menunjukkan derajat (extent) dan
kecepatan (rate) absorpsi yang
ekivalen dibandingkan dengan produk
komparatornya

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Pemberlakuan syarat bioekivalensi

 Secara umum berlaku untuk sediaan obat generik/


obat copy untuk pemberian secara ekstravaskular
dengan efek sistemik, dalam bentuk padat (termasuk
suspensi)
 Di Indonesia masih dibatasi:
 Obat baru
 Golongan obat tertentu (antibiotika, obat jantung,
obat antihipertensi)
 Sediaan obat tertentu (modified release)
 Di Indonesia ada SK Badan POM, ada masa transisi

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 Uji BA-BE adalah persyaratan mutu obat yang
berhubungan dengan efikasi obat
 Dimensi mutu obat itu sendiri mencakup:
 Keamanan (Safety)
 Kemanjuran (Efficacy)
 Stabilitas
 Kemudahan/kenyamanan penggunaan
 Reliability

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Tahapan proses obat dalam tubuh

 Pelepasan, disolusi,
difusi, transfer dan
absorpsi merupakan
proses
Pelepasan
Disolusi
Difusi
HATI
Absorpsi
biofarmasetik.
Metabolisme EMPEDU
Ekskresi

RESEPTOR

PARU-PARU  Absorpsi, distribusi,


metabolisme dan
ekskresi, merupakan
JANTUNG
JARINGAN

GINJAL
proses
Distribusi farmakokinetik
Ekskresi

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Persyaratan mutu obat & Perkembangannya

(Khusus persyaratan biofarmasetik yang resmi/wajib)

Contoh untuk sediaan Tablet (proses yang kompleks):


 Uji Waktu Hancur in vitro (1934-1970)
 Uji Disolusi in vitro (1970, USP XVIII)
 Uji BA-BE in vivo (di Indonesia sejak tahun 2005-an)

-> Perkembangan terjadi karena terjadinya


perkembangan dalam ilmu Biofarmasi (dan
Farmakokinetik)

9
25
0%
20 25%
50%
Kadar (m g/mL)

75%
15
100%

10

0
0 4 8 12 16 20 24

Waktu (jam)

 Perkembangan kadar kloramfenikol dalam plasma setelah pemberian


suspensi kloramfenikol palmitat dalam dosis tunggal 150 mg dengan
campuran polimorf A dan B (Aguiar et al., 1967).

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Kenapa terjadi perkembangan?

 Pada masa lalu belum terdeteksi adanya masalah


 Hasil-hasil yang dilakukan
 Ditunjang oleh kemajuan dalam bidang lain
(Farmakokinetika, Farmasi Analisis)

 Perkembangan akan selalu terjadi

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Aturan terakhir PERSYARATAN BIOEKIVALENSI

 Peraturan Kepala Badan POM RI Tahun 2011 tentang


Obat Wajib Uji Ekivalensi (Uji BE atau Uji Disolusi
Terbanding atau UDT)
 Wajib uji ekivalensi berlaku untuk sediaan obat
generik atau ‘Obat Copy’ dalam bentuk sediaan
tertentu yang memiliki potensi masalah ketersediaan
hayatinya (seperti dijelaskan dalam Pedoman Uji
Bioekivalensi)
 Masih terbatas untuk golongan obat tertentu (10
golongan obat + sediaan obat lepas termodifikasi +
obat copy pertama)

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10 GOLONGAN OBAT WAJIB UJI BE

 ANTIDIABETES
 ANTITROMBOTIK
 OBAT KARDIOVASKULAR (Anti-aritmia & Anti-angina)
 ANTIHIPERTENSI (Diuretik dll.)
 PENURUN KADAR LIPID
 OBAT KONTRASEPSI
 OBAT SALURAN KEMIH
 ANTI-INFEKSI
 OBAT OSTEOPOROSIS
 OBAT SISTEM SYARAF PUSAT

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Kenapa uji ekivalensi untuk Obat Generik?

 Karena obat generik tidak melalui uji klinik, lain


halnya dengan produk innovator
 Obat generik menggunakan sumber bahan baku zat
aktif, formulasi dan teknik pembuatan sediaan yang
kemungkinan besar berbeda dengan yang digunakan
oleh produk innovator
 Karakteristik bahan baku zat aktif yang digunakan,
formulasi dan teknik pembuatan sediaan berpengaruh
terhadap ketersediaan hayati obat

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Bagaimana pelaksanaan uji bioekivalensi?
Ada aturan-aturan yang harus diikuti:
 Produk komparator
 Sistem untuk pengujian (test system): Subyek serta
jumlahnya
 Desain uji (crossover, parallel, replicate design; single
dose, multiple dose; puasa atau bersama makanan)
 Kondisi subyek saat pemberian obat dan selama pengujian
 Cara uji (farmakokinetik atau farmakodinamik)
 Jenis sampel untuk pengujian (darah atau urin atau
lainnya) dan waktu sampling
 Parameter yang dinilai (Cmaks, AUC, atau lainnya) serta
cara evaluasinya
 Penarikan kesimpulan: Perhitungan confidence interval
rasio
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Kenapa obat generik disyaratkan BE
 Efek yang dihasilkan oleh suatu zat aktif pada proses
terapi berhubungan dengan kadar zat aktif yang
sampai ke reseptor (ketersediaan hayati)
 Ketersediaan hayati zat aktif dari suatu sediaan obat
dipengaruhi oleh sejumlah faktor farmasetik:
 Sifat fisiko-kimia zat aktif (ukuran partikel, bentuk
kristal, dll.)
 Faktor formulasi
 Faktor teknik pembuatan
 Faktor farmasetik obat generik tidak sama dengan
produk innovator
 Data similaritas disolusi (in vitro) tidak menjamin
bioekivalensi produk
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Pedoman pelaksanaan uji BE
 Test Drug (Obat Uji)
 Reference Drug (Komparator)
 Subject
 Study design (experimental design)
 Sample to be collected
 Analyte
 Sampling time
 Assay method
 Parameters to be analysed
 Evaluation method
 In Vitro Dissolution Tests
 Study Report
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Test Drug

 The test product used in the study should be


representative of the product to be marketed
 The test product should usually originate from a
batch of at least 1/10 of production scale or 100,000
units, whichever is greater, unless otherwise
justified.
 The reference and test products should be packed in
an individual way for each subject and period, either
before their shipment to the trial site, or at the trial
site itself. Packaging (including labelling) should be
performed in accordance with good manufacturing
practice

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Reference Drug

 Reference/Comparator drug : corresponding dosage


form of an medicinal product.
 The choice of comparator innovator product should be
justified by the applicant and agreed upon by the
regulatory authority.
 If the innovator product is not available, an
alternative comparator product approved by drug
regulatory authority of the country can be used.
Generic drug which is on the market of ICH countries and
associated countries or WHO PQ can be accepted. However, if
there is no generic drug in ICH countries and its associated
countries neither generic drug of WHO PQ, using registered
generic drug in the country which is BE to its innovator product
that has been proven can be considered.
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OBAT KOMPARATOR

(1) Obat Komparator yang digunakan dalam Uji


Ekivalensi harus obat inovator yang memiliki Izin
Edar di Indonesia.
(2) Dalam hal obat inovator sebagaimana dimaksud pada
ayat (1) berasal dari tempat produksi yang berbeda
dengan tempat produksi obat inovator yang terdaftar
di Indonesia, maka harus dilakukan Uji Disolusi
Terbanding untuk membuktikan ekivalensi kedua
obat inovator.

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(3) Jika Obat Komparator sebagaimana dimaksud pada
ayat (1) tidak tersedia, maka dapat dipilih dengan
urutan prioritas sebagai berikut:
a. Obat yang telah terdaftar di negara yang tergabung
dalam International Conference on Harmonization
(ICH) dan negara asosiasinya (associated countries);
b. Obat Copy yang telah terbukti bioekivalen
terhadap obat inovator dengan hasil paling
mendekati obat inovator; atau
c. Obat yang termasuk dalam daftar prakualifikasi
World Health Organization (WHO).

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Strength to be investigated

 The bioequivalence study should in general be


conducted at the highest strength. For products with
linear pharmacokinetics and where the drug
substance is highly soluble (see Appendix III),
selection of a lower strength than the highest is also
acceptable. Selection of a lower strength may also be
justified if the highest strength cannot be
administered to healthy volunteers for
safety/tolerability reasons.

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Study design

 If two formulations are compared, a randomised, two-


period, two-sequence single dose crossover design is
recommended. The treatment periods should be
separated by a wash out period sufficient to ensure
that drug concentrations are below the lower limit of
bioanalytical quantification in all subjects at the
beginning of the second period. Normally at least 5
elimination half-lives are necessary to achieve this.

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Subjects

Subjects
The subject population for bioequivalence studies should be
selected with the aim of permitting detection of differences
between pharmaceutical products. In order to reduce variability
not related to differences between products, the studies should
normally be performed in healthy volunteers unless the drug
carries safety concerns that make this unethical.

Number of subjects
The number of subjects to be included in the study should be
based on an appropriate sample size calculation. The number of
evaluable subjects in a bioequivalence study should not be less
than 12.

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Faktor yang menentukan jumlah subyek

 Nilai variansi parameter yang ada (CV


intrasubyek)
 Aras keberartian atau significance level
()
 Power ()
 Besarnya perbedaan parameter yang
dihasilkan oleh obat uji dan obat
komparator

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Perhitungan jumlah subyek

 µT adalah nilai rata-rata parameter ketersediaan hayati untuk


produk uji
 µR adalah nilai rata-rata parameter ketersediaan hayati untuk
produk komparator
 CV adalah CV intrasubyek
 α adalah aras keberartian (5%,)
 β adalah power (20%)
 Z adalah nilai z dari kurva normal baku sesuai luas dari aras
keberartian atau power
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Sample

 In bioequivalence studies, the plasma concentration


time curve is generally used to assess the rate and
extent of absorption.
 In certain situation, urine sample can be accepted.

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Analyte(s)

 In principle, evaluation of bioequivalence should be based upon


measured concentrations of the parent compound.
 Also for inactive prodrugs, demonstration of bioequivalence for
parent compound is recommended.
 The use of a metabolite as a surrogate for an active parent
compound is not encouraged. This can only be considered if the
applicant can adequately justify that the sensitivity of the
analytical method for measurement of the parent compound
cannot be improved and that it is not possible to reliably
measure the parent compound after single dose administration
taking into account also the option of using a higher single dose
in the bioequivalence study

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Sampling time

 A sufficient number of samples to adequately describe the


plasma concentration-time profile should be collected.
 The sampling schedule should include frequent sampling around
predicted tmax to provide a reliable estimate of peak exposure.
In particular, the sampling schedule should be planned to avoid
Cmax being the first point of a concentration time curve.
 The sampling schedule should also cover the plasma
concentration time curve long enough to provide a reliable
estimate of the extent of exposure which is achieved if AUC(0-t)
covers at least 80% of AUC(0-∞). (min 3 T1/2)
 At least three to four samples are needed during the terminal
log-linear phase in order to reliably estimate the terminal rate
constant (which is needed for a reliable estimate of AUC(0-∞)).

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Test conditions

 The test conditions should be standardised in order


to minimise the variability of all factors involved
except that of the products being tested. Therefore,
it is recommended to standardise diet, fluid intake
and exercise.
 The time of day for ingestion should be specified.
Subjects should fast for at least 8 hours prior to
administration of the products, unless otherwise
justified. As fluid intake may influence gastric
passage for oral administration forms, the test and
reference products should be administered with a
standardised volume of fluid (at least 150 ml).

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Assay method

 The bioanalytical methods used must be well


characterised, fully validated and documented to
yield reliable results that can be satisfactorily
interpreted. Within study validation should be
performed using Quality control samples in each
analytical run.
 The main characteristics of a bioanalytical method
that is essential to ensure the acceptability of the
performance and the reliability of analytical results
are: selectivity, lower limit of quantitation, the
response function (calibration curve performance),
accuracy, precision and stability.

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Parameters to be analysed

For plasma sample :


 Cmax or Cmax, ss
 AUC (0-t) or AUC (0-72)
 AUC(0-∞)
 AUC(0- )
 Tmax or Tmax, ss

For urine sample :


 Ae(0-t) or Ae(0-t)
 Rmax

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AUC(0-∞) = AUC (0-t) + Ct/slope

AUC (0-t) dihitung dengan metode


trapezium

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Evaluation

 Calculation of 90% confidence interval for the ratio of


the test and reference products should be contained
within the acceptance interval of 80.00-125.00%.
 For studies to determine bioequivalence of immediate
release formulations at steady state, AUC(0-τ) and
Cmax,ss should be analysed using the same
acceptance interval as stated above.
 In the rare case where urinary data has been used,
Ae(0-t) should be analysed using the same acceptance
interval as stated above for AUC(0-t). Rmax should be
analysed using the same acceptance interval as for
Cmax.

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IN VITRO DISSOLUTION TESTS

 The results of in vitro dissolution tests at three


different buffers (normally pH 1.2, 4.5 and 6.8) and
the media intended for drug product release (QC
media), obtained with the batches of test and
reference products that were used in the
bioequivalence study should be reported.
 Particular dosage forms like ODT (oral dispersible
tablets) may require investigations using different
experimental conditions.
 The results should be reported as profiles of percent
of labelled amount dissolved versus time displaying
mean values and summary statistics.

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STUDY REPORT

 The report of the bioequivalence study should give


the complete documentation of its protocol, conduct
and evaluation.
 It should be written in accordance with the ICH E3
guideline (in Indonesia follows ASEAN format of BA-
BE Study Report) and be signed by the investigator in
accordance with Annex I of the Directive 2001/83/EC
as amended.

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ORGANISATION OF BE LAB

 Clinical Part (conforms to GCP)


 Analytical Part (conforms to GLP)

In Indonesia:
 For GLP requirement, a BE Lab/Center should be
acredited by International Standar(ISO 17025)
 For GCP requirement, BE Labs/Centers are audited by
National Body for Drug and Food Control (Badan
Pengawas Obat dan Makanan)

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BA-BE Labs/Centers in Indonesia (approved)

 BELabs
 Clinisindo
 Econolab International
 Equilab International
 Faculty of Pharmacy University of Indonesia
 Omega
 Pharma Metric Laboratory (PML)
 SanClinEq

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Proses pelaksanaan uji BE
 Permintaan Sponsor ke Lab BE (SPK)
 Lab BE menyusun protokol, menyiapkan metode
analisis
 Persetujuan Komisi Etik (Lab BE, presentasi di Komisi
Etik)
 Permohonan dan persetujuan PPUB ke Badan POM
(Sponsor)
 Pelaksanaan uji BE oleh Lab BE (recruitment subyek,
sampling, analisis sampel BE, pengolahan data
(perhitungan parameter BE, analisis statistik)
 Pembuatan Laporan Uji BE (Lab BE, format ASEAN)
 Penyampaian hasil uji BE ke Badan POM (Sponsor)
 Pengakuan Badan POM
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Pendekatan menuju BE

Pendekatan profil disolusi


Target: Similar dengan produk
innovator (faktor F2)

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Permasalahan yang dihadapi

 Fakta: banyak pengalaman produk


similar secara disolusi tetapi tidak
bioekivalen
 Terjadi perubahan proses biofarmasetik
(profil disolusi?) pada saat up-scaling

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Antisipasi terjadinya kerugian yang lebih besar
akibat tidak BE

 Dilakukan uji pilot sebelum uji BE yang


sebenarnya dilakukan
 Untuk menghindari kerugian karena tidak BE, uji
BE dilakukan bertahap: Tahap 1 minimal 12
subyek

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